12-57225391-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007224.4(NXPH4):​c.571C>A​(p.Pro191Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,596,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

NXPH4
NM_007224.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.264
Variant links:
Genes affected
NXPH4 (HGNC:8078): (neurexophilin 4) Predicted to enable signaling receptor binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.080827475).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NXPH4NM_007224.4 linkuse as main transcriptc.571C>A p.Pro191Thr missense_variant 2/2 ENST00000349394.6 NP_009155.1
NXPH4XM_017018747.2 linkuse as main transcriptc.400+171C>A intron_variant XP_016874236.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NXPH4ENST00000349394.6 linkuse as main transcriptc.571C>A p.Pro191Thr missense_variant 2/21 NM_007224.4 ENSP00000333593 P1
NXPH4ENST00000555154.1 linkuse as main transcriptn.622C>A non_coding_transcript_exon_variant 2/23
NXPH4ENST00000556415.1 linkuse as main transcriptc.*698C>A 3_prime_UTR_variant, NMD_transcript_variant 3/32 ENSP00000452288

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151616
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000969
AC:
14
AN:
1444492
Hom.:
0
Cov.:
31
AF XY:
0.00000836
AC XY:
6
AN XY:
717906
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151616
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74090
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000834
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2022The c.571C>A (p.P191T) alteration is located in exon 2 (coding exon 2) of the NXPH4 gene. This alteration results from a C to A substitution at nucleotide position 571, causing the proline (P) at amino acid position 191 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0091
T
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.41
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.081
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
0.58
N
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.054
Sift
Benign
0.082
T
Sift4G
Uncertain
0.013
D
Polyphen
0.0
B
Vest4
0.20
MutPred
0.47
Gain of catalytic residue at L189 (P = 0);
MVP
0.14
MPC
0.95
ClinPred
0.16
T
GERP RS
-1.9
Varity_R
0.14
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781063753; hg19: chr12-57619174; API